Sexual Dysfunction (SD) is described as a disorder of or an interruption in sexual functioning. In women, the most common type of sexual disorder is generalized, acquired HSDD defined by the Diagnostic and Statistical Manual, 4th Edition, Text Revision (American Psychiatric Association, 2000; DSM-IV-TR) as: “The persistent lack (or absence) of sexual fantasies or desire for any form of sexual activity marked by distress or interpersonal difficulty and not better accounted for by another disorder (except another sexual dysfunction) direct physiological effects of a substance (including medications) or a general medical condition.” The presence of distress or interpersonal difficulty is an integral part of sexual disorders and is central to the diagnosis of the condition. Approximately 1 in 10 women reported low sexual desire with associated distress, which may be HSDD.
Synonyms for HSDD include sexual aversion, i.e., extreme aversion to, absence of, and avoidance of all, or almost all, sexual contact with a partner; inhibited sexual desire; sexual apathy; loss of libido; decreased sexual desire; distressing loss of sexual desire; and sexual anorexia. HSDD occurs in both sexes. It is considered to be the most common of all female sexual disorders, possibly occurring in as many as 10% of women in the United States.
In women, a majority of HSDD cases are generalized in subtype, though a substantial minority of cases may relate to dissatisfaction or loss of interest in the sexual partner. Either subtype of HSDD can lead to general feelings of dissatisfaction in the person and/or discord in their personal relationships, including for example marital discord. Sexual disorders, whether generalized or situational, often do not respond to counseling therapy, and frequently culminate in separation, finding a new sexual partner, and divorce.
The other phases of sexual function, sexual arousal and orgasm, are also subject to impairment. In women, dysfunctions in these sexual phases, if sufficiently distressing, are known, respectively, as Female Sexual Arousal Disorder (FSAD) and Female Orgasmic Disorder (FOD) in DSM-IV-TR. Collectively, they impair sexual function in almost as many women as does HSDD (Shifren J L et al, Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008 November; 112(5):970-81. Women in the peri- and post-menopause are the most affected subpopulation with such problems. In the US, in the age group 45-64 years, the prevalence of FSAD is about 3.1 million; of FOD, 2.4 million. Little overlap of these disorders was found in the largest, most representative survey of women's sexual function (the PRESIDE study, Shifren et al, ibid.), so the overall number of US women affected with FSAD or FOD is over 5 million.
In men, dysfunction in arousal (in erection) is well recognized; dysfunctional delay in, or absence of, orgasm (ejaculation) also occurs with some frequency. If it causes significant sexual distress, the disorder is called Male Orgasmic Disorder (MOD; delayed ejaculation). Male dysfunctionally premature ejaculation (PE) is much more frequent than any of these problems, occurring in up to 30% of younger men (Laumann et al., Sexual dysfunction in the United States: Prevalence and predictors, JAMA, 1999; 281:537-44).
Sexual dysfunction may also be manifested as a significant burden in the course of physical diseases. Sexual dysfunction is frequent in women with chronic, fatiguing medical illness, especially Female HSDD or FSAD due to breast cancer, diabetes mellitus, or irritable bowel syndrome or due to combined factors including one of these medical diseases. These conditions occur mainly in middle-aged to older patients. Collectively, these conditions cause sexual dysfunction, mainly desire disorder, in over 7.8 million women age 45-64 in the US (breast or gynecologic cancer, 1.5 million; diabetes, at least 3.4 million; irritable bowel, at least 2.9 million). SD in Men with chronic diseases is little studied but can be presumed from the ample evidence on women to be another large set of clinically and epidemiologically significant health problems. The most authoritative arbiter of diagnostic names and criteria on sexual dysfunction, the DSM-IV-TR, recognizes eight kinds of sexual disorders due to chronic physical disease: Sexual Dysfunction due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer); Female HSDD due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer); Male HSDD due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer); Male Erectile Disorder due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer); Female Dyspareunia due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer); Male Dyspareunia due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer); Other Female Sexual Dysfunction due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer) if some other feature is predominant (e.g., Orgasmic Disorder) or no feature predominates; and Other Male Sexual Dysfunction due to General Medical Conditions (e.g., irritable bowel syndrome, diabetes, cancer) if some other feature is predominant (e.g., Orgasmic Disorder) or no feature predominates.
Collectively, in this document, all of the sexual dysfunctions and disorders described above are called sexual dysfunctions, sexual disorders, or SD.
As there is no currently approved treatment for HSDD or any other sexual disorder except (male) erectile dysfunction in the United States, a therapeutic composition and methods for ameliorating sexual disorders is an unmet need for a significant portion of the population and their quality of life. Delineated herein are compositions and methods of treatment that may be useful to address this unmet need based on heretofore unexpected properties possessed by the subject compositions.
Erectile Dysfunction (ED) is the only male sexual dysfunction for which pharmacotherapies are broadly available. Sexual disorders other than ED, e.g., HSDD, are also common in men, although research on non-ED male sexual disorders has lagged compared to that in women. However, the cross-national US survey published in 1999 by Laumann et al. showed that male lack of interest in sex, at 15% of men aged 18-59, was about as frequent as erectile dysfunction (18%). In March (Derogatis et al, J Sex Med 2012; 9:812-820), a research group applied a battery of validated scales to men with HSDD vs. those with no sexual dysfunction. The men with HSDD had dramatic impairments on all rating scales relating to HSDD: on the Sexual Concerns Index-Male, a measure of male sexual distress; the UCLA Psychosexual Diary's measure of sexual activity; and the Male Desire Scale, a measure of sexual desire; but did not have ED: [International Index of Erectile Function (IIEF)-5 median score] or depression [Beck Depression scale] or low testosterone: men with low or low-normal testosterone levels (<300 ng/dL) were excluded. Their data show that male HSDD is a real problem of clinical magnitude. *p<0.0001 for each variable; sample sizes were about 100
No pharmacologic treatment is available in most countries including the US for either men or women with sexual disorders other than for men with ED, although a testosterone transdermal system was approved for women with postmenopausal HSDD in Europe in 2005.
Yet another male sexual dysfunction is frequent, though not the subject of a DSM-IV-TR diagnosis: Male sexual performance anxiety was a problem for 17% of US men age 18-59 in the cross-national survey published by Laumann in 1999 in JAMA, about the same incidence as for erectile dysfunction (ED) and male lack of sexual interest. Male sexual performance anxiety was about twice as prevalent as ED in US men under age 50. It is little studied but can cause significant distress, especially in male patients in infertility clinics. Peterson B D, Newton C R, and Feingold T. in “Anxiety and sexual stress in men and women undergoing infertility treatment,” in Fertility and Sterility 2007 October; 88(4):911-4, Epub 2007 Apr. 11, found in a prospective study at a University-affiliated teaching hospital for in vitro fertilization and intrauterine insemination (306 women, 295 men) a strong linkage between anxiety and sexual stress in men and concluded that sexual stress among infertile men may be more closely tied to performance anxiety rather than to a more general deterioration in sexual satisfaction associated with infertility.
Male sexual performance anxiety, while not a disorder recognized in DSM-IV-TR or ICD-10, is recognized as a necessary focus in the recommended clinical evaluation of men with sexual dysfunction according to the Third International Consultation on Sexual Medicine (Paris, July 2009). Hatzichristou D, Rosen R C, Derogatis L R, et al, Recommendations for the Clinical Evaluation of Men and Women with Sexual Dysfunction, J Sex Med 2010; 7:337-348. These experts recommend diagnostic workup for male sexual performance anxiety because it may cause or result from the recognized male sexual disorders such as ED (psychogenic impotence) and premature ejaculation.
The model of sexual functioning that is most accepted is one in which sexual desire leads to arousal, and eventually orgasm. Even E D, currently the most treatable of sexual dysfunctions, is unlikely to be aided by pharmacotherapy unless desire can be restored. Thus, loss of desire is of primary concern for treating all disorders of sexual function.
The current invention relates to combinations of a 5-HT1A receptor agonist and/or 5-HT2A receptor antagonist (e.g., trazodone, nefazodone, mirtazapine, flibanserin), a norepinephrine-dopamine reuptake inhibitor (e.g., bupropion), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) and their use to augment sexual desire, arousal, and orgasm. Their ability to help men feel desire will also aid male sexual performance anxiety. These combinations will be particularly effective for each of these disorders in men and women because they will allow the corrective effects of the individual agents to become manifest without being masked by the side effects of either drug, and in particular it will allow rapid relief of symptoms because the effective dose can be given immediately due to the low expected side effects, instead of requiring weeks of up-titration to overcome side effects over time. This makes Lorexys®, a fixed combination of bupropion and trazodone, of special value for male HSDD and sexual performance anxiety as disorders that cause distress and disrupt quality of life on the days when a man is to have sex with a partner.
The current invention relates to combinations of a 5-HT1A receptor agonist and/or 5-HT2A receptor antagonist (e.g., trazodone, nefazodone, mirtazapine, flibanserin ketanserin, ritanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100,907, cyproheptadine, aripiprazole, and the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines), a norepinephrine-dopamine reuptake inhibitor (e.g., bupropion), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) and their use to augment sexual desire, arousal, and orgasm. Their ability to help men feel desire will also aid male sexual performance anxiety. These combinations will be particularly effective for each of these disorders in men and women because they will allow the corrective effects of the individual agents to become manifest without being masked by the side effects of either drug, and in particular it will allow rapid relief of symptoms because the effective dose can be given immediately due to the low expected side effects, instead of requiring weeks of up-titration to overcome side effects over time. This makes Lorexys®, a fixed combination of bupropion and trazodone, of special value for male HSDD and sexual performance anxiety as disorders that cause distress and disrupt quality of life on the days when a man is to have sex with a partner.
The current invention also relates to combinations of a 5-HT1A receptor agonist and/or 5-HT2A receptor antagonist (e.g., trazodone, nefazodone, mirtazapine, flibanserin ketanserin, ritanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100,907, cyproheptadine, aripiprazole, and the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines), and/or a 5-HT2C receptor antagonist, and/or a 5HT-2c receptor agonist, (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, and metachlorophenylpiperazine, mCPP), a norepinephrine-dopamine reuptake inhibitor (e.g., bupropion), and/or other non-abusable agents (agents not scheduled by the DEA) that augment dopamine and/or norepinephrine in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, talopram, talsupram, tandamine, viloxazine, maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's wort, ginkgo biloba), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) and their use to augment sexual desire, arousal, and orgasm. Their ability to help men feel desire will also aid male sexual performance anxiety. These combinations will be particularly effective for each of these disorders in men and women because they will allow the corrective effects of the individual agents to become manifest without being masked by the side effects of either drug, and in particular it will allow rapid relief of symptoms because the effective dose can be given immediately due to the low expected side effects, instead of requiring weeks of up-titration to overcome side effects over time. This makes Lorexys®, a fixed combination of bupropion and trazodone, of special value for male HSDD and sexual performance anxiety as disorders that cause distress and disrupt quality of life on the days when a man is to have sex with a partner.
Disorders of cognition are also frequent, and are of particular concern because of their high prevalence in older patients (an enlarging segment of the population), the disability they cause, and their intractability to current treatments. Improvement in cognition as augmentation of cognition for therapeutic purposes is also of interest, e.g., in the circumstances of subjects whose cognitive skills are limiting for tasks that require learning or vigilance. The invention provides a method of treating a subject suffering from or susceptible to a cognitive disorder or otherwise in need of improvement in cognition with a composition comprising a 5-HT1A agonist, a 5-HT2A antagonist, a norepinephrine-dopamine reuptake inhibitor, an oxytocin receptor (OXTR) agonist, and a pharmaceutically acceptable carrier.
Depressive disorders are also frequent (lifetime risk in women, 10-25%; in men, 5-12%) and are of particular concern because of the disability they cause, the high likelihood of failure with initial treatment (only about 50% of patients with Major Depressive Disorder respond to any one antidepressant, the high frequency of incomplete response to currently available treatments (only about 30% of patients achieve full remission with a given antidepressant), their increasing frequency of treatment-resistance, and especially because they often lead to suicide, in about 15% of patients (DSM-IV-TR). The invention provides a method of treating a subject suffering from or susceptible to a depressive disorder comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a 5-HT1A agonist, a 5-HT2Aantagonist, a norepinephrine-dopamine reuptake inhibitor, an oxytocin receptor (OXTR) agonist, and a pharmaceutically acceptable carrier.
It is not readily apparent from published literature reports that oxytocin (OT) can relieve human sexual dysfunction. Though a case report of pro-sexual effects of transnasal OT has been published for each of three very different patients [a postpartum woman without sexual dysfunction: Anderson-Hunt and Dennerstein, Brit Med J. 1994; 309:929; an elderly man with orgasmic disorder: IsHak et al., J Sex Med. 2008; 5:1022-4, and a complex psychiatric patient without sexual dysfunction: MacDonald and Feifel, J Sex Med 2012; 9:1407-1410], the only published placebo-controlled study showed no significant advantage for oxytocin: 24 International Units (IU) of intranasal OT failed to increase arousal or orgasm in men on the primary outcome scale, the “Acute Sexual Experiences Scale (ASES).” The authors concluded that “the effects of OT on sexual behavior were equivocal . . . ” [Burri et al, Psychoneuroendocrinology. 2008; 33:591-600.] Also, in the most recent review of the side effects of transnasal OT, in which almost a thousand subjects were treated with OT (Syntocinon® in almost all studies) in controlled studies to investigate non-sexual effects, no events of any type of increase in sexual function were reported [MacDonald et al, Psychoneuroendocrinology. 2011 September; 36(8):1114-26].
However, OT mediates pro-social and anti-anxiety effects, doing so through effects on the amygdala in a placebo-controlled study. [Kirsch et al., J. Neuroscience 2005; 25(49):11489-11493]. It is a novel aspect of the invention that these properties will specifically aid all DSM-IV-TR-recognized sexual dysfunction disorders listed as having the DSM-IV-TR subtype “due to situational factors,” i.e., in men or women who are in a relationship in which sexual activity has deteriorated in frequency and/or satisfaction because of increasing loss of trust and/or anxiety about performance, avoidance patterns etc., that occur as a consequence of any of the recognized sexual dysfunction disorders: in the male partner, HSDD, ED, PE, MOD, and dyspareunia, and in (the epidemiologically frequent but not DSM-IV-recognized condition of) male sexual performance anxiety; in the female partner, HSDD, FSAD, FOD, and dyspareunia. It is a novel aspect of the invention that the same properties of oxytocin, aiding trust and reducing social anxiety, will aid most of the other subtypes of each of these disorders of sexual function, i.e., the subtypes “due to psychological factors and “due to combined factors.” “Situational” is defined in DSM-IV-TR as applying “if the sexual dysfunction is limited to certain types of stimulation, situations, or partners,” which is the opposite of the Generalized type. “Due to Psychological Factors” applies “when psychological factors are judged to have the major role in the onset, severity, exacerbation, or maintenance of the Sexual Dysfunction . . . . ” “Due to Combined Factors” is defined as applying “when psychological factors are judged to have a role in the onset, severity, exacerbation, or maintenance of the Sexual Dysfunction . . . . ”
It is a novel aspect of the invention that oxytocin is useful to treat the aforementioned subtypes of every diagnostic category of sexual dysfunction. Drawing on clinical experience in couples having a long-term partnered relationship, sexual dysfunction in one partner ordinarily worsens because of the other partner's reaction over time to that sexual dysfunction, and can cause sexual dysfunction in the partner, too. For example, generalized HSDD in a woman is likely to lead her to non-receptivity, which may lead her to a psychosocially destructive pattern of avoidance behavior regarding potential sexual situations. The male partner learns to avoid sexual frustration, anger, arguments etc. by also practicing avoidance behavior. At first this may simply be sublimation, but the likely result over time is atrophy of all sexual aspects of the union, including sexual dysfunction in the male partner—performance anxiety likely occurring first, then HSDD, ED, and/or PE. That leads to further decline in the sexual relationship. The woman's HSDD was originally, and logically remains, generalized. But both partners' sexual disorders may then alternatively be subtyped as situational, due to psychological factors, or due to combined factors.
Similarly, it is another aspect of the invention that oxytocin specifically aids all additionally proposed DSM-5 sexual dysfunction disorders (Male HSDD, Erectile Disorder, Delayed Ejaculation, Female Sexual Interest/Arousal Disorder, Genito-Pelvic Pain/Penetration Disorder, Substance/Medication-Induced Sexual Dysfunction, and Sexual Dysfunction Not Elsewhere Classified) with the proposed Specifiers of Situational, Partner factors (e.g., partner's sexual problems, partner's health status), and Relationship factors (e.g., poor communication, discrepancies in desire for sexual activity). [www.dsm5.org, Aug. 2, 2012].
The current invention relates to combinations of a 5-HT1A receptor agonist, 5-HT2A receptor antagonist, 5-HT2C receptor antagonist, or combinations thereof (e.g., trazodone). The current invention also relates to combinations of a 5-HT1A receptor agonist, 5-HT2A receptor antagonist, 5-HT2C receptor antagonist, or combinations thereof (e.g., trazodone), and a norepinephrine-dopamine reuptake inhibitor (e.g. bupropion), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) to augment cognition, improve failing mental processes in cognitive disorders, and improve mood and the depressive symptoms that accompany mood disorders. The current invention also relates to combinations of a 5-HT1A receptor agonist, 5-HT2A receptor antagonist (e.g., trazodone, nefazodone, mirtazapine, flibanserin), a norepinephrine-dopamine reuptake inhibitor (e.g. bupropion), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) to augment cognition, improve failing mental processes in cognitive disorders, and improve mood and the depressive symptoms that accompany mood disorders. These combinations are particularly effective for each of these disorders as they allow the corrective effects of the individual agents to become manifest without being masked by the side effects of either drug, and in particular it allow rapid relief of symptoms because the effective dose can be given immediately due to the low expected side effects, instead of requiring weeks of up-titration to overcome side effects over time. Reduced toxicity is provided by a compound of the invention when administered in vivo, e.g., formulating bupropion, by itself a mild stimulant, with trazodone, by itself a moderate sedative, in the proprietary ratio of Lorexys, will neutralize the main side effects of each of the two drugs. This makes Lorexys®, a fixed combination of bupropion and trazodone, of special value for treating acute symptoms such as suicidality, disabling symptoms such as inability to work or otherwise function, especially for older patients who generally are more prone to side effects and for whom adverse effects cause more risk, and especially because such a combination can be prescribed by a health provider with less specialized expertise in pharmacologic treatment of neuro-psychiatric disorders.
The current invention relates to combinations of a 5-HT1A receptor agonist, 5-HT2A receptor antagonist, 5-HT2C receptor antagonist, or combinations thereof (e.g., trazodone, nefazodone, mirtazapine, flibanserin ketanserin, ritanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100,907, cyproheptadine, aripiprazole, and the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). The current invention also relates to combinations of a 5-HT1A receptor agonist, 5-HT2A receptor antagonist, 5-HT2C receptor antagonist, or combinations thereof (e.g., trazodone), and a norepinephrine-dopamine reuptake inhibitor (e.g. bupropion), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) to augment cognition, improve failing mental processes in cognitive disorders, and improve mood and the depressive symptoms that accompany mood disorders. The current invention also relates to combinations of a 5-HT1A receptor agonist, 5-HT2A receptor antagonist (e.g., trazodone, nefazodone, mirtazapine, flibanserin), a norepinephrine-dopamine reuptake inhibitor (e.g. bupropion), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) to augment cognition, improve failing mental processes in cognitive disorders, and improve mood and the depressive symptoms that accompany mood disorders. These combinations are particularly effective for each of these disorders as they allow the corrective effects of the individual agents to become manifest without being masked by the side effects of either drug, and in particular it allow rapid relief of symptoms because the effective dose can be given immediately due to the low expected side effects, instead of requiring weeks of up-titration to overcome side effects over time. Reduced toxicity is provided by a compound of the invention when administered in vivo, e.g., formulating bupropion, by itself a mild stimulant, with trazodone, by itself a moderate sedative, in the proprietary ratio of Lorexys, will neutralize the main side effects of each of the two drugs. This makes Lorexys®, a fixed combination of bupropion and trazodone, of special value for treating acute symptoms such as suicidality, disabling symptoms such as inability to work or otherwise function, especially for older patients who generally are more prone to side effects and for whom adverse effects cause more risk, and especially because such a combination can be prescribed by a health provider with less specialized expertise in pharmacologic treatment of neuro-psychiatric disorders.
The current invention also relates to combinations of a 5-HT1A receptor agonist and/or 5-HT2A receptor antagonist (e.g., trazodone, nefazodone, mirtazapine, flibanserin ketanserin, ritanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100,907, cyproheptadine, aripiprazole, and the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines), and/or a 5-HT2C receptor antagonist, and/or a 5HT-2c receptor agonist, (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, and metachlorophenylpiperazine, mCPP), a norepinephrine-dopamine reuptake inhibitor (e.g., bupropion), and/or other non-abusable agents (agents not scheduled by the DEA) that augment dopamine and/or norepinephrine in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, talopram, talsupram, tandamine, viloxazine, maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's wort, ginkgo biloba), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) to augment cognition, improve failing mental processes in cognitive disorders, and improve mood and the depressive symptoms that accompany mood disorders. The current invention also relates to combinations of a 5-HT1A receptor agonist, 5-HT2A receptor antagonist (e.g., trazodone, nefazodone, mirtazapine, flibanserin), a norepinephrine-dopamine reuptake inhibitor (e.g. bupropion), and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon®) to augment cognition, improve failing mental processes in cognitive disorders, and improve mood and the depressive symptoms that accompany mood disorders. These combinations are particularly effective for each of these disorders as they allow the corrective effects of the individual agents to become manifest without being masked by the side effects of either drug, and in particular it allow rapid relief of symptoms because the effective dose can be given immediately due to the low expected side effects, instead of requiring weeks of up-titration to overcome side effects over time. Reduced toxicity is provided by a compound of the invention when administered in vivo, e.g., formulating bupropion, by itself a mild stimulant, with trazodone, by itself a moderate sedative, in the proprietary ratio of Lorexys, will neutralize the main side effects of each of the two drugs. This makes Lorexys®, a fixed combination of bupropion and trazodone, of special value for treating acute symptoms such as suicidality, disabling symptoms such as inability to work or otherwise function, especially for older patients who generally are more prone to side effects and for whom adverse effects cause more risk, and especially because such a combination can be prescribed by a health provider with less specialized expertise in pharmacologic treatment of neuro-psychiatric disorders.